5-HT2A serotonin receptors represent the principal neuropharmacological target for LSD-like hallucinogens and an important molecular target for many psychiatric medications (e.g. selected atypical antipsychotics, antidepressants and atypical anxiolytics). Not surprisingly, 5-HT2A receptors continue to be actively targeted for psychiatric drug discovery in many therapeutic areas including schizophrenia, sleep disorders and cognition enhancement. Thus, study of 5-HT2A receptors is likely to lead to novel insights into psychiatric drug actions as well as insights into the molecular mechanisms responsible for psychosis and related disorders. We have recently discovered that 5-HT2A receptors functionally interact with RSK-2 and that knocking-out RSK-2 augments 5-HT2A mediated signaling (see Preliminary studies). These results imply that the psychosis and impaired cognition, which occur in Coffin-Lowry Syndrome, are due, in part, to over-active 5-HT2A signaling. In favor of this hypothesis are findings that 5-HT2A receptor agonists induce psychosis and cognitive impairment reminiscent of schizophrenia in humans and that 5-HT2A antagonists improve cognition and reduce psychosis in schizophrenia. For more than 50 years it has been suggested that the psychosis, which occurs in schizophrenia is due, in part, to dysregulation of serotonergic signaling-without any direct evidence. These findings represent the first direct evidence in favor of the hypothesis that psychosis is associated with augmented 5-HT2A receptor signaling. The ultimate goal of these studies is to elucidate the molecular actions by which 5-HT2A receptors are regulated and targeted to neuronal subdomains and how this system is dysregulated in various psychotic states: Specific Aim 1: To determine the relevance of 5-HT2A receptor interactions with PDZ-domain containing proteins on the functional activity and sorting of 5-HT2A receptors in vitro and, ultimately, in vivo. Specific Aim 2: To determine the relevance of 5-HT2A receptor interactions with caveolins-1 and flotillin, which target 5-HT2A receptors. Specific Aim 3: To determine whether the interaction between ribosomal S6-kinase-2 (RSK2) and 5-HT2A receptors has functional significance.